Cyclohexanecarboxylic acid → HCID 90015380, compound

Temperature

80 °C

To a 20 ml screw cap vial was charged 2-bromo-5-methyl-pyridine (50 mg, 0.3 mmols, 1 equiv.), (tert-butyl 4-(2-aminopyridin-4-yl)piperidine-1-carboxylate (113 mg, 0.4 mmols, 1.4 equiv.), sodium tert-butoxide (40.3 mg, 0.40 mMols, 1.4 equiv.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (25.7 mg, 0.045 mmols, 0.15 equiv.) and tris(dibenzylideneacetone)dipalladium(0 (26.8 mg, 0.03 mmols, 0.1 equiv.). The contents were dissolved in 5 ml of anhydrous dioxane, capped, vortexed for 10 seconds and shaken at 80° C. for 18 h. The crude was filtered, concentrated and dissolved in ethyl acetate (10 ml), washed with water (once), brine (once) and dried over sodium sulfate. The organic was concentrated, dissolved in dichloromethane (10 ml) and hydrogen chloride gas was bubbled through for 30 seconds and capped. The reaction was shaken until complete (45 mins) and concentrated. To a solution of the crude in anhydrous dimethylformamide (3 ml) was added cyclohexanecarboxylic acid (44.7 mg, 0.36 mmols, 1.2 equiv.), triethylamine (91 mg, 0.9 mmols, 3 equiv.) and finally O-Benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate (167 mg, 0.42 mmols, 1.4 equiv.). The vial was capped and shaken at 45° C. for 18 h. The mixture was concentrated, dissolved in ethyl acetate (10 ml) and washed with 1N sodium hydroxide (once), water (once), brine (once), dried over sodium sulfate and concentrated. The crude was evaporated to dryness, dissolved into dimethylformamide (1 ml) and purified by reverse phase HPLC (basic conditions) to give cyclohexyl(4-(2-((5-methylpyridin-2-yl)amino)pyridin-4-yl)piperidin-1-yl)methanone (47.4 mg, 42% yield). 1H NMR (400 MHz, DMSO-d6) δ 9.43 (d, J=3.2 Hz, 1H), 8.10-8.03 (m, 2H), 7.57 (d, J=5.8 Hz, 2H), 6.75-6.72 (m, 3H), 4.65-3.69 (m, 3H), 3.07-2.58 (m, 5H), 1.93-1.24 (m, 11H).

1. customTo a 20 ml screw cap vial
2. customcapped
3. filtrationThe crude was filtered
4. concentrationconcentrated
5. dissolutiondissolved in ethyl acetate (10 ml)
6. washwashed with water (once), brine (once) and
7. dry with materialdried over sodium sulfate
8. concentrationThe organic was concentrated
9. dissolutiondissolved in dichloromethane (10 ml)
10. customhydrogen chloride gas was bubbled through for 30 seconds
11. customcapped
12. stirringThe reaction was shaken until complete (45 mins)
13. concentrationconcentrated
14. customThe vial was capped
15. stirringshaken at 45° C. for 18 h
16. concentrationThe mixture was concentrated
17. dissolutiondissolved in ethyl acetate (10 ml)
18. washwashed with 1N sodium hydroxide (once), water (once), brine (once),
19. dry with materialdried over sodium sulfate
20. concentrationconcentrated
21. customThe crude was evaporated to dryness
22. dissolutiondissolved into dimethylformamide (1 ml)
23. custompurified by reverse phase HPLC (basic conditions)

ORD record

ord-2cbd8ca8d27144b1937c290f90c4e8aa

Source dataset

uspto-grants-2016_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09399636B2